Abstract
We investigated the acute effects of the immunosuppressive agent, tacrolimus (FK-506), on the exocrine pancreas, in rats with or without stimulation of the pancreas, in rats with or without stimulation of the pancreas, and evaluated the protective effects exerted by gabexate mesilate (FOY). While an intravenous injection of FK-506 did not change serum amylase levels during the 5-h observation period, this agent increased pancreatic amylase and protein content, and decreased the content of pancreatic DNA. Histologically, we observed intra-acinar vacuolization and individual cell necrosis. When the pancreas was stimulated by two intraperitoneal injections of caerulein (5 μg/kg) at 1-h intervals, however, which treatment did not induce any evident pancreatic change, FK-506 significantly increased serum amylase, pancreatic wet weight, and pancreatic amylase and protein, and decreased pancreatic DNA. Histologically, there were significant dose-related differences in the severity of intra-acinar vacuolization, interstitial edema, neutrophil infiltration, individual cell necrosis, and hemorrhage. Levels of intrapancreatic elastase were elevated and local pancreatic blood flow was reduced. Treatment with FOY improved the FK-506-induced acute pancreatitis, but did not increase the pancreatic blood flow. These findings indicate that FK-506 enhances abnormal pancreatic enzyme secretion and suggest that therapeutic doses of this agent can induce acute pancreatitis when the pancreas is stimulated. A protease inhibitor may protect the exocrine pancreas in patients who receive FK-506 after organ transplantation.
This is a preview of subscription content, log in via an institution to check access.
References
Kino T, Hatanaka H, Hashimoto M, et al. FK-506, a novel immunosuppressant isolated from astreptomyces. 1. Fermentation, isolation, and physico-chemical and biological characteristics. J Antibiot 1987;40:1249–1255.
Starzl TE, Fung J, Venkataramanan R, et al. FK-506 for liver, kidney and pancreas transplantation. Lancet 1989;11:1000.
Kino T, Hatanaka H, Hashimoto M, et al. FK-506, a novel immunosuppressant isolated from astreptomyces. II. Immunosuppressant effect of FK-506 in vitro. J Antibiot 1987;40: 1256–1265.
Todo S, Demetris JA, Ueda Y, et al. Renal transplantation in baboons under FK-506. Surgery 1989;106:444–450.
Ochiai T, Sakamoto K, Gunji Y, et al. Effects of combination treatment with FK-506 and cyclosporine on survival time and vascular changes in renal allograft-recipient dogs. Transplantation 1989;48:193–197.
Nalesnik MA, Todo S, Murase N, et al. Toxicology of FK-506 in the Lewis rat. Transplant Proc 1987;19:89–92.
Ohara K, Billington R, James RW, et al. Toxicologic evaluation of FK-506. Transplant Proc 1990;22:83–86.
Yoshimura N, Nakai I, Ohmori Y, et al. Effect of cyclosporine on the endocrine and exocrine pancreas in kidney transplant recipients. Am J Kidney Dis 1988;11:11–17.
Lober MI, Buren CTV, Flechner SM, et al. Hepatobiliary and pancreatic complications of cyclosporine therapy in 466 renal transplant recipients. Transplantation 1987;43:35–40.
Watson CJE, Jamieson NV, Johnston PS, et al. Early abdominal complications following heart and heart-lung transplantation. Br J Surg 1991;78:699–704.
Ito T, Kimura T, Yamaguchi H, et al. Acute pancreatitis induced by cyclosporin A under stimulation of pancreas by caerulein. Pancreas 1993;8(6):693–699.
Yamaguchi H, Kimura T, Mimura K, et al. Activation of proteases in caerulein-induced pancreatitis. Pancreas 1989;4: 565–571.
Aukland K, Bower BF, Berliner RW. Measurement of local blood flow with hydrogen gas. Circulation Res 1964;14:164–187.
Ceska M, Birath K, Brown B. A new and rapid method for the clinical determination of α-amylase activities in human serum and urine. Clin Chim Acta 1969;26:437–444.
Lowry OH, Rosebrough NJ, Farr AL. Protein measurement with the Folon phenol reagent. J Biol Chem 1951;127:182–186.
Burton K. A study of the conditions and mechanism of the diphenylamine reaction for the colorimetric estimation of deoxyribonucleic acid. Biochem J 1956;62:315–323.
Giles KW, Myers A. An improved diphenylamine method for the estimation of deoxyribonucleic acid. Nature 1965;206:93.
Bieth J, Spiess B, Wermuth CG. The synthesis and analytical use of a highly sensitive and convenient substrate of elastase. Biochem Med 1974;11:350–357.
Wallenstein S, Zucker CL, Fleiss JL. Some statistical methods useful in circulation method. Circulation Res 1980;47:1–9.
Lampel M, Kern HF. Acute interstitial pancreatitis in the rat induced by excessive doses of a pancreatic secretagogue. Virchows Arch [A] 1977;373:97–117.
Doi R, Tangoku A, Inoue K, et al. Effects of FK-506 on exocrine pancreas in rats Pancreas 1992;7:197–204.
Jordan ML, Shapiro R, Fung J, et al. Intial studies with FK-506 in renal transplantation. Cleve Clin J Med 1991;58:444–446.
Creutzfelt W, Schmit H. Aetiology and pathogenesis of pancreatitis. Scand J Gastroenterol 1970;6:47–62.
Demetris AJ, Fung JJ, Todo S, et al. Pathogenic observation in human allograft recipients treated with FK506. Transplant Proc 1990;22:25–34.
Haba T, Hashisuka T, Ohtsuka Y, et al. Pathological immunohistochemical examination in the rat treated wtih FK506. Transplant Proc 1991;23:2229–2232.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Ito, T., Kimura, T., Furukawa, M. et al. Protective effects of gabexate mesilate on acute pancreatitis induced by tacrolimus (FK-506) in rats in which the pancreas was stimulated by caerulein. J Gastroenterol 29, 305–313 (1994). https://doi.org/10.1007/BF02358370
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF02358370